Tailing oligonucleotide analogues with hydrophobic molecules may facilitate the entry of the oligonucleotide conjugates into living cells and, thereby, improve the potency of antisense molecules in inhibiting gene expression. However, the size of the PEG conjugated to oligonucleotides may adversely affect the hybridization properties of the conjugates. An in vitro assay has been developed to evaluate the hybridization abilities of PEG-oligonucleotide conjugates with a complementary HIV-TAR RNA oligomer (250 nt.). The synthesis of oligodeoxyribonucleotides using a solid support derivatized with PEG (M.W.: 300, 2,000 or 5,000) has unexpectedly been facile. Conversely, the condensation of activated PEG-derivatives with the 5'-end of an oligonucleotide anchored to a solid support has been difficult. In this regard, significant progress has, however, been achieved through the use of solid-phase bound oligonucleotides derivatized with novel nucleophilic linkers. Although, the hybridization of PEG-oligonucleotide conjugates with complementary DNA sequences having equal number of nucleobases was not affected by the size of the PEG tail, PEG-oligonucleotide conjugates did not hybridize as well with the 250 bases long RNA oligomer. Digestion of hybrids composed of PEG-oligonucleotide conjugates and radiolabelled HIV- TAR RNA with ribonuclease A and ribonuclease T1 showed that the oligonucleotide conjugated with the PEG (M.W. 5,000) did not significantly hybridize with the RNA relative to an unmodified DNA oligomer. While the oligonucleotide conjugated with PEG (M.W. 300) hybridized as well as the parent oligonucleotide with the target RNA, the oligonucleotide conjugated to PEG (M.W. 2,000) hybridized to the extent of ca. 50% with HIV-TAR RNA under the same conditions. The above assay did not, however, provide evidence indicating that the PEG portion of the conjugate could have wrapped around or entangled with the RNA as a means to further suppress translation. It is, nevertheless likely that PEG should protect the oligonucleotide moiety of the conjugates against exonucleases. The potency of an alpha,beta-oligodeoxyribonucleotide conjugated to PEG (M.W. 300) toward the inhibition of HIV replication in a chronically infected human T-cell line is being evaluated.